The impact of influenza infection is felt globally each year when the disease develops in approximately 20% of the world's population. Influenza A virus, in particular, represents a significant health risk to the public. This is due both to its ability to spread quickly within human populations and the high degree of mortality associated with infection. In the last century, three influenza A pandemics in 1918, 1957 and 1968 killed cumulatively over 50 million people. The highly pathogenic H5N1 strain of influenza A virus is emerging as the most likely cause of the world's next major influenza pandemic.
Influenza viruses belong to the family Orthomyxoviridae, and are divided into three (3) genera: Influenza A, Influenza B, and Influenza C. Influenza A can cause of epidemics and pandemics in humans and may be transmitted through an avian intermediate host. Influenza B can causes epidemics and has no intermediate host. Influenza C does not occur in epidemics and causes mild disease.
Influenza A viruses are further classified based on the identity of two surface glycoproteins: hemagglutinin and neuraminidase. Nine subtypes of influenza neuraminidases are known, N1 to N9, and sixteen subtypes of hemagglutinin are known, H1 to H16. Thus, influenza A H5N1 refers to an influenza virus which contains H5 subtype hemagglutinin and N1 subtype neuraminidase.
Neuraminidase cleaves the specifc linkage of the sialic acid receptor in the cell membrane, resulting in the release of the newly formed virions from the infected cells. In addition, neuraminidase may function to facilitate the early process of influenza virus infection of lung epithelial cells. Hence, neuraminidase inhibitors have been an attractive target for the development of novel anti-influenza drugs. Use of effective neuraminidase inhibitors can serve an important role in the early containment of influenza outbreaks in the human population and would complement widespread use of new avian influenza vaccines. Influenza neuraminidases are classified within two categories: group-1 and group-2. Group-1 contains N1, N4, N5, and N8 subtypes, and group-2 contains N2, N3, N6, N7, and N9.
Existing influenza medicines include oseltamivir (Tamiflu®) and zanamivir (Relenza). These function by inhibiting neuraminidase. However, there have been several documented cases of the emergence of resistance to these drugs by several different sub-strains of avian flu H5N1. Also, the FDA has recently issued a warning label for Tamiflu® after reports of serious psychiatric side-effects in patients receiving the drug, especially children. These factors suggest that there is a significant clinical need for new influenza drugs, particularly to contain the avian flu virus strain H5N1, with improved properties (including efficacy, selectivity and reduced sensitivity to resistance) relative to the current marketed drugs.